Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Binding of plasmin(ogen) to rat C6 glioma cells is saturable and kringle-domain dependent. This interaction was studied as a model of plasmin(ogen) receptor interactions in nucleated mammalian cells. Apparent 125I-plasmin dissociation from C6 cell binding sites was slow; however, the dissociation rate was increased when the solution contained diisopropyl phosphoryl-plasmin (0.3 microM), fibrinogen (0.16 or 0.8 mg/ml), 1.08 mM D-Val-L-Leu-L-Lys-p-nitroanilide-HCl (S-2251), or epsilon-amino-n-caproic acid (EACA, 5.0 mM). EACA promoted the most rapid dissociation of plasmin. C6 cell-associated plasmin and plasmin in solution demonstrated similar amidase activity. Only specifically bound plasmin (75% of total binding) was active against S-2251. Plasmin that was initially bound to C6 cells digested fibrinogen in a time- and plasmin concentration-dependent manner. alpha 2-Antiplasmin (alpha 2AP, 0.1 microM) completely inhibited fibrinogenolysis by plasmin that was initially C6- or human umbilical vein endothelial-cell associated. Since alpha 2AP reacts selectively with plasmin in solution (minimally with plasmin bound to cells), fibrinogen digestion by cell-associated plasmin probably occurred only after the plasmin dissociated into solution. Crosslinked fibrin clots were formed in uniform layers over C6 cells. If the cells were incubated with plasmin before addition of fibrinogen and thrombin, the clots were rapidly lysed. alpha 2AP incompletely inhibited fibrinolysis when added after fibrin polymerization (44% inhibition with 0.1 microM alpha 2AP). Fibrinolysis was completely inhibited when alpha 2AP was added before fibrin polymerization. These studies suggest that plasmin must first dissociate from cellular binding sites to mediate fibrinogenolysis or fibrinolysis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Fibrinogenolytic and fibrinolytic activity of cell-associated plasmin. 767 97

Localization of the plasminogen binding sites on fibrin has been difficult since these interactions occur on polymerizing fibrin, and studies with fragments can be misleading because of multiple carboxyl-terminal lysines that may bind to plasminogen. A hetero-functional photoaffinity cross-linker was used to study these interactions. Following attachment of the cross-linker to plasminogen in the dark, a clot was formed by addition of fibrinogen or fragment X and thrombin, and then the plasminogen was cross-linked to adjacent parts of fibrin by exposure to light. There was more Glu1-plasminogen bound to fibrin than to fibrinogen and more to fragment X polymer than to fibrin. Electron microscopy of rotary shadowed individual molecules reveals that Glu1-plasminogen appears to be more compact than Lys78-plasminogen or Glu1-plasminogen with 6-aminohexanoic acid. Cross-linked complexes from the dissolved clot observed by electron microscopy reveal plasminogen bound to the end of fibrin or bridging the ends of two fibrin molecules; larger complexes were also observed. Analysis of changes in the appearance of negatively contrasted fibers with plasminogen bound also indicates the probable locations of binding sites, yielding results consistent with the cross-linking studies. The photoaffinity probe was also used to study interactions between plasminogen and fibrin or its derivatives in the course of tissue plasminogen activator-mediated fibrinolysis. Samples cross-linked at various times indicate that complexes with fragment X are particularly dominant during the rapid phase of plasminogen activation. In conclusion, these studies indicate that plasminogen binds to the pocket at the end-to-end junction between two fibrin or fragment X molecules in the protofibril; from this position, it can reach all of the sites that are cleaved during fibrinolysis.
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PMID:Interactions of plasminogen with polymerizing fibrin and its derivatives, monitored with a photoaffinity cross-linker and electron microscopy. 828 11

The interactions of fucoidan with glutamic plasminogen (Glu-Plg), two-chain tissue plasminogen activator (t-PA), LMwt-urokinase, thrombin, and antithrombin III (AT-III) were investigated using fucoidan-sepharose affinity chromatography. The results showed 1) a high degree of affinity between fucoidan-sepharose and Glu-Plg; Lmwt-urokinase and thrombin while t-Pa and AT-III did not bind with fucoidan-sepharose. 2) The double reciprocal plot for the LMwt-urokinase activation of Glu-Plg showed that plasminogen activator inhibitor (PAI-1) inhibited this reaction in a noncompetitive manner and that the presence of fucoidan decreased Km for this interaction by 50% and increased Kcat by 30-fold, 3) The double reciprocal plot for the t-PA activation of Glu-Plg showed that PAI-1 inhibited this reaction in a competitive manner and that fucoidan in conjunction with 6-aminohexanoic acid (6-AH) increased Kcat for this interaction by 5-fold without affecting Km. 4) Fucoidan enhanced the interaction of thrombin with both AT-III and heparin cofactor II (HC-II) and it was more effective than unfractionated heparin of LMwt-heparin in enhancing the interaction of HC-II with thrombin.
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PMID:Interaction of fucoidan with proteases and inhibitors of coagulation and fibrinolysis. 930 16

The interaction of lipoprotein(a) [Lp(a)] with platelets is not well defined, particularly with regards to the individual contribution of the protein components of Lp(a), the apo B-100 and the apolipoprotein apo(a). This study investigated the binding of different recombinant apo(a) [r-apo(a)] isoforms, to human platelets and its effect on platelet aggregation. Scatchard analysis of saturation binding experiments demonstrated that human platelets display a single class of high affinity r-apo(a) binding sites (71 +/- 46 molec./platelet, Kd = 5.6 +/- 2.0 nmol/L). Platelet activation with strong agonists (thrombin, arachidonic acid) increased 2- to 10-fold the r-apo(a) binding, without affecting the affinity. Competition assays showed that the binding sites are highly specific for r-apo(a) and Lp(a). At high concentration t-PA could also bind to the r-apo(a) binding sites. By contrast, neither fibrinogen nor plasminogen inhibited to the r-apo(a) binding. The lysine analogue EACA inhibits the binding of r-apo(a) to platelets, thus suggesting the involvement of lysine residues in that interaction. Moreover, the r-apo(a) binding to platelets is unlikely mediated by GPIIb/IIIa-attached fibrin since it is not affected by platelet treatment with either LJ-CP8, a monoclonal antibody that specifically blocks fibrinogen binding to GPIIb/IIIa, nor GPRP, an inhibitor of fibrin polymerisation. Finally, we show that the distinct recombinant apo(a) proteins, as well as native Lp(a), promote an aggregation response of platelets to otherwise subaggregant doses of arachidonic acid. This proaggregant effect of r-apo(a) is dependent on its binding to platelets since it requires a minimum incubation time, and it is prevented by EACA at concentration inhibiting the r-apo(a)-platelet interaction. These results suggest that the prothrombotic action of Lp(a) may be in part mediated by modulating the platelet function through the interaction of its apo(a) subunit with a specific receptor at the platelet surface.
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PMID:Binding of recombinant apolipoprotein(a) to human platelets and effect on platelet aggregation. 1134 6

The developments and trends of hemostatic and antithrombotic drugs in Japan were investigated chronologically for the last 50 years after the 2nd World War. 1. Hemostatic drugs are classified into three groups ; capillary stabilizers, blood coagulants and antifibrinolytics. l) As to capillary stabilizers, flavonoid (rutin, 1949), adrenochrome derivative (carbazochrome, 1954) and conjugated estrogen (Premarin, 1964) were introduced therapeutically. Especially, the soluble types of adrenochrome compounds (Adona 1956, S-Adchnon, 1962) were devised and used widely in Japan. 2) Drugs concerning blood coagulation, thrombin, introduced in 1953, and hemocoagulase, a snake venom introduced in 1966, were used clinically. V.K. groups producing various coagulation factors were introduced as V.K1 (Phytonadione, 1962) and V.K2 (rnenatetrenone,1972), and they were admitted in "The Japanese Pharmacopoeia"editions 8 and 14, respectively). 3) Regarding antifibrinolytic drugs, Japanese researchers have made remarkable contributions. e-Aminocapronic acid (Ipsilon, 1962) and tranexamic acid (Transamin, 1965) were developed and used for various abnormal bleedings or hemorrhage associated with plasmin over-activation. tranexamic acid also proved to suppress inflammations of the throat such as tonsillitis, pharyngitis or laryngitis. 2. Antithrombotic drugs are also divided into three groups; anticoagulants, antiplatelet drugs and fibrinolytics.1) The anticoagulants used therapeutically by injection are heparins (Na-salt, 1951; Ca-salt, 1962) and low-molecular-weight heparins such as dalteparin (1992), parnaparin (1994) and reviparin (1999). The low molecule compounds are superior to the original heparins in reducing the risk of bleeding. As oral anticoagulants, coumarin derivatives, dicumarol (1950), ethylbiscoumacetate (1954), phenylindandione (1956) and warfarin (1962) are known. Warfarin potassium is the main drug for oral therapy of thromboembolism lately. Gabexate mesilate (1989) and nafamostat mesilate (1989) were developed in Japan and used for DIC and acute pancreatitis to inhibit protease enzymes. Argatroban is a unique antithrombin product developed by Japanese researchers in 1990, and is used for vascular or cerebral thrombosis. After noticing in 1968 that aspirin inhibits platelet aggregation and prevents myocardial infraction, projects for developing antiplatelet drugs were initiated worldwide. Ticlopidine, originally developed in France, was introduced in 1981 and prevailed widely in Japan for reducing the risk of thrombotic stroke. Aspirin itself was recognized by the FDA (USA) as an antithrombotic drug in 1988, and was also approved by Japanese authorities in 2000. PGE1 clathrate compounds have also been developed as antiplatelet drugs; alprostadil alfadex for injection (1979), and limaprost alfadex for oral use (1988). The PGI2 product, beraprost sodium, for oral use followed them in 1992. Other antiplatelet drugs with unique mechanisms explored in Japan: Ozagrel (1988), which inhibits TXA2 synthetase, cilostazol (1988), which inhibits cAMP phosphodiesterase, and sarpogrelate (1993), which blocks 5HT in platelets, are the notable drugs in this field. Ethyl icosapentate, from fish oil, is available for antiplatelet therapy. Concerning the fibrinolytic system, plasminogen activators are useful for thromboembolism. The streptokinase from bacterial origin developed in the USA and Europe was not introduced, and urokinase (1965) was the first plasminogen activator developed in Japan. Then tissue plasminogen activators (t-PA) tisokinase (cell culture, 1991), alteplase (genetical recombination, 1991), nateplase (genetical recombination, 1996), monteplase (1998) and pamiteplase (1998) were developed and approved for acute myocardial infarction. Nasaruplase (prourokinase, cell culture,1991) was also approved for the same indication. While the development of the hemostatic drugs ceased in the 1960s, avid project studies for antithrombotic drugs including fibrinolytics began in the 1980s and are progressing now towards new molecular targets. This may be due to the increasing tendency of cardiovascular thromboembolic diathesis in Japan. (The figures in parentheses are the years approved by the Japanese Ministry of Health, Labor and Welfare.)
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PMID:[A 50-year history of new drugs in Japan-the development and trends of hemostatics and antithrombotic drugs]. 1457 69

epsilon-Aminocaproic acid (EACA) is a synthetic low molecular drug with antifibrinolytic activity. However, treatment with this drug can be incidentally associated with an increased thrombotic tendency. The aim of the present work was to test synthetic EACA derivatives for their antiplatelet activities. We investigated the effect of three EACA derivatives with antifibrinolytic activity: I. epsilon-aminocaproyl-L-leucine hydrochloride (HCl*H-EACA-L-Leu-OH), II. epsilon-aminocaproyl-L-(S-benzyl)-cysteine hydrochloride (HCl*H-EACA-L-Cys(S-Bzl)-OH) and III. epsilon-aminocaproyl-L-norleucine (H-EACA-L-Nle-OH) on platelet responses (aggregation and adhesion) and on their integrity. It was found that: 1. as judged by LDH release test, none of the tested compounds, up to 20 mM, was toxic to platelets, 2. in comparison with EACA, all the synthetic derivatives inhibited much stronger the ADP- and collagen-induced aggregation of platelets suspended in plasma (platelet rich plasma) and aggregation of these cells in whole blood, 3. EACA and its derivatives exerted a similar inhibitory effect on the thrombin-induced adhesion of platelets to fibrinogen-coated surfaces. Since platelet activation and blood coagulation are tightly associated processes, the antiplatelet properties of EACA derivatives are expected to indicate reduced thrombotic properties of these derivatives compared to EACA.
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PMID:The effect of some epsilon-aminocaproic acid derivatives on platelet responses. 1509 27

Enoxaparin (Lovenox; Roule-Poulenc Rorer, Inc.), a low molecular weight heparin (LMWH), is commonly used in the management of non-ST-segment elevation acute coronary syndromes (NSTE ACS) based on clinical trial outcomes. It is one of a group of glycosaminoglycan compounds that accelerate the inactivation of factor Xa by inducing a conformational change in antithrombin. In contrast to unfractionated heparin (UFH), LMWH have greater bioavailability, a more predictable anticoagulant response, longer half-life and a higher proportion of anti-factor Xa to anti-factor IIa activity. As a consequence, laboratory monitoring of the anticoagulant effect is typically unnecessary. Antithrombin therapy with LMWH or UFH has the highest-level recommendation (IA) in the 2002 professional guidelines for the management of unstable angina and non-ST-elevation myocardial infarction, where enoxaparin has a IIA recommendation over UFH unless early coronary artery bypass surgery is planned. In a recent systematic overview of > 20,000 patients with NSTE ACS from six clinical trials, including conservative and invasively managed patients, enoxaparin provided a statistically significant reduction in 30-day death or nonfatal myocardial infarction (MI) compared with UFH with no significant excess in transfusions, or major bleeding. These data support the role of enoxaparin as an anti-coagulant in patients with NSTE ACS.
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PMID:Clinical use of enoxaparin in the management of non-ST segment elevation acute coronary syndromes. 1595 76

Non-ST elevation Acute Coronary Syndrome (NSTE-ACS) is a myocardial ischemic disorder frequently caused by coronary artery plaque rupture and partial or transient vessel occlusion. Platelets and thrombin play pivotal roles in formation and propagation of thrombus at the site of plaque disruption and embolization into the vascular bed. With the outgoing development of antithrombotic, antiplatelet, and mechanical therapies, the management of NSTE-ACS is constantly evolving. Heparins are the cornerstone of antithrombotic therapy in the current management of NSTE-ACS. Unfractionated heparin and fractionated heparins like enoxaparin have been studied in several large clinical trials and found to be effective in reducing death and myocardial infarction rates. For medical management alone or primarily (conservative strategy), enoxaparin has been shown to be superior to unfractionated heparin. With an early invasive strategy providing better clinical outcome compared to a conservative strategy, the paradigm of ACS management has shifted in favor of early (within 48 hours of admission) cardiac catheterization. The effectiveness of enoxaparin compared to unfractionated heparin is now being re-considered in the era of poly-pharmacotherapy and an early invasive strategy for ACS management. We review the role of enoxaparin in the contemporary treatment of NSTE-ACS utilizing recent clinical trial data.
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PMID:Enoxaparin in clinical practice and clinical trials of non-ST-elevation Acute Coronary Syndrome (NSTE-ACS). 1605 1

The composition of an atherosclerotic plaque is an important determinant of plaque stability. Unstable rupture-prone plaques are characterized by a thin fibrous cap that contains few muscle cells. Several lines of evidence suggest that macrophage activation in the unstable shoulder of the plaque could contribute to plaque rupture by releasing toxic factors, possibly nitric oxide (NO), to smooth muscle cells. These macrophages are also involved in the uptake of apoptotic cells (AC) and the inefficient removal of the latter might contribute to the formation of the necrotic core through accumulation of necrotic debris. Furthermore, these AC rapidly expose phosphatidylserine on their surface, which is a potent substrate for the generation of thrombin and activation of the coagulation cascade. The following new insights in the etiopathogenesis of atherothrombosis will be discussed: (1) Human atherosclerotic plaques contain amyloid precursor protein (APP) and beta-amyloid peptide, which is cleaved from APP and which has been extensively studied in Alzheimer's disease. Macrophages phagocytose platelets,which contain APP in their alpha-granules and this platelet derived APP is subsequently proteolytically processed in these macrophages into beta-amyloid The latter is involved in the upregulation of the inducible NO-synthase which results in an increased production of toxic amounts of NO. (2) Phagocytosis of the pro-coagulant ACS is severely impaired in advanced human atherosclerotic plaques. Several factors present in the atherosclerotic lesion,such as accumulation of indigestible material in the macrophage cytoplasm,oxidative stress,and the presence of oxidized LDL or oxidized erythrocytes may contribute to the impairment of phagocytosis. (3) In order to study the impact of the impaired phagocytosis by the macrophages on the atherosclerotic lesion development,a double knock-out mouse was created which spontaneously develops atherosclerosis combined with a deficient phagocytotic capacity. Completely unexpected the double-knock out mouse developed an until now not described phenotype resembling the metabolic syndrome including a spectacular increase in body weight,accumulation of abdominal fat and fat in the liver and increased plasma levels of cholesterol. Furthermore the atherosclerotic lesions demonstrated a striking different morphology as compared to the lesions present in mice which spontaneously develop atherosclerosis.
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PMID:[New insights into the etiopathogenesis of atherosclerosis and atherothrombosis]. 1717 27

Non-ST elevation acute coronary syndrome (NSTE-ACS) refers to a cardiovascular disorder characterized by intracoronary thrombus formation on a disrupted atherosclerotic plaque with partial or transient occlusion. Generation of thrombin resulting from exposure of collagen leads to activation of platelets and conversion offibrinogen to fibrin, thus forming a platelet-rich thrombus. The main therapeutic objective is to protect the patient from thrombotic complications, independent of the choice of antithrombotic agents. The management of NSTE myocardial infarction (MI) is constantly evolving. For primarily conservative strategy, enoxaparin has been proven superior to unfractioned heparin (UFH). With early invasive strategy providing better clinical outcome compared with conservative strategy, the effectiveness of enoxaparin in reducing death and MI rates is now being reconsidered in the era of poly-pharmacotherapy, early percutaneous coronary interventions and drug eluting stents. Bleeding complications can be minimized by avoiding cross-over from UFH to enoxaparin or vice versa, or by reducing the dosage of enoxaparin. We review the studies of enoxaparin and discuss its current role in the contemporary treatment of NSTE-ACS.
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PMID:Enoxaparin injection for the treatment of high-risk patients with non-ST elevation acute coronary syndrome. 1758 Jul 32


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